Studies in this group have focused on the mechanisms that control the fate of newly synthesized proteins after their insertion into the membrane of the endoplasmic reticulum (ER). Analysis of the fate of unassembled chains of multiprotein complexes demonstrated the existence of a pathway for the degradation of proteins retained within the ER. Our studies have now defined the nature of structural determinants for retention and degradation within the ER for a number of proteins and have provided direct evidence for the localization of this degradation pathway to the ER system. Transmembrane domains containing one or more potentially charged or highly polar amino acid residues, termed "heterophilic membrane sequences", were found to act as determinants of retention and degradation in the ER. In addition to subunits of certain multiprotein complexes, this structural motif was identified within precursors of glycophosphatidylinositol anchored proteins, where it was also shown to play a role in ER retention and degradation. The development of a permeabilized cell system to study ER degradation allowed characterization of the intracellular location and biochemical properties of the pathway. Degradation was shown to occur under conditions in which there is no transport between the ER and the Golgi system, implying that the ER itself is capable of effecting protein degradation.